Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

• Published in: Annals of neurology Vol. 86; no. 5; pp. 714 - 728
• Main Authors: Lévesque, Maxime, Chen, Li‐Yuan, Etter, Guillaume, Shiri, Zahra, Wang, Siyan, Williams, Sylvain, Avoli, Massimo
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.11.2019; Wiley Subscription Services, Inc
• Subjects: Animals; CA3 Region, Hippocampal - physiopathology; Convulsants - toxicity; Convulsions & seizures; Epilepsy; Epilepsy, Temporal Lobe - chemically induced; Epilepsy, Temporal Lobe - physiopathology; Interneurons; Interneurons - physiology; Male; Mice; Mice, Transgenic; Optogenetics; Oscillations; Parvalbumin; Pilocarpine; Pilocarpine - toxicity; Ripples; Seizures; Seizures - chemically induced; Seizures - physiopathology; Spikes; Stimulation; Temporal lobe; Transgenic mice
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25572

Objective To establish the effects induced by long‐term, unilateral stimulation of parvalbumin (PV)‐positive interneurons on seizures, interictal spikes, and high‐frequency oscillations (80–500Hz) occurring after pilocarpine‐induced status epilepticus (SE)—a proven model of mesial temporal lobe epilepsy (MTLE)—in transgenic mice expressing or not expressing ChR2. Methods PV‐ChR2 (n = 6) and PV‐Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450nm, 25mW, 20‐millisecond pulses delivered at 8Hz for 30 seconds every 2 minutes) of CA3 PV‐positive interneurons was implemented for 14 continuous days in both groups. Results Rates of seizures (p < 0.01), interictal spikes (p < 0.001), and interictal spikes with fast ripples (250–500Hz) (p < 0.001) were lower in PV‐ChR2 than in PV‐Cre mice. Ripples (80–200Hz) occurring outside of interictal spikes had higher rates in the PV‐ChR2 group (p < 0.01), whereas isolated fast ripples had lower rates (p < 0.01). However, seizure probability was higher during optogenetic stimulation in PV‐ChR2 compared to PV‐Cre animals (p < 0.05). Interpretation Our findings show that the unilateral activation of CA3 PV‐positive interneurons exerts anti‐ictogenic effects associated with decreased rates of interictal spikes and fast ripples in this MTLE model. However, PV‐positive interneuron stimulation can paradoxically trigger seizures in epileptic animals, supporting the notion that γ‐aminobutyric acid type A signaling can also initiate ictogenesis. ANN NEUROL 2019;86:714–728